There have been published the following patent applications drawn to xanthine oxidase inhibitors. For example, Japanese Patent Unexamined Publication No. 95272/1984 discloses 3-phenylpyrazole derivatives having a xanthine oxidase inhibitory activity, Japanese Patent Unexamined Publication No. 85379/1982 discloses 3-phenylisothiazole derivatives having a xanthine oxidase inhibitory activity, WO92/09279 discloses 2-phenylthiazole derivatives having a xanthine oxidase inhibitory activity, and Japanese Patent Unexamined Publication No. 211815/1994 discloses 3-phenylisoxazole derivatives having xanthine oxidase inhibitory activity. While Japanese Patent No. 2504659 discloses 1-phenylpyrazolecarboxylate that is used as a synthetic intermediate for drugs, it does not disclose its xanthine oxidase inhibitory activity or use as a therapeutic agent of hyperuricacidemia and gout.
The hyperuricacidemia and gout (acute arthritis) resulting therefrom are highly frequently found in middle-aged males. It is said that the numbers of old patients and younger patients are on the rise due to diverse eating habits of these days. A therapeutic agent of hyperuricacidemia includes uricosuric agents and uric acid synthesis inhibitors, and is selected depending on the disease state of hyperuricacidemia. As the uricosuric agent, benzbromarone, probenecid and sulfinpyrazone have been used, while as the uric acid synthesis inhibitor, allopurinol alone has been used. This allopurinol is a stereoisomer of hypoxanthine and inhibits xanthine oxidase. This inhibition leads to the suppression of uric acid production and decrease in blood uric acid level However, allopurinol is known to cause side effects such as hypersensitive symptoms (e.g., anthema, hives and the like) or renal and hepatic disorders. In particular, the hypersensitive symptoms has been reported to be caused by a metabolite of allopurinol, such as oxypurinol [The American Journal of Medicine, vol. 76, p. 47 (1984)]. Thus, it appears that a compound having a structure not analogous to hypoxanthines has a potential of avoiding side effects.
Therefrom it is suggested that a compound having a novel structure not analogous to hypoxanthine and showing xanthine oxidase inhibitory activity will make a therapeutic agent with less side effects for hyperuricacidemia and gout Thus, the present invention aims at providing a therapeutic agent for hyperuricacidemia and gout, which has a strong xanthine oxidase inhibitory activity and a sustained lowering action on uric acid level in blood, and which causes less side effects as compared to conventional compounds.
Meanwhile, generation of active oxygen has been documented to be responsible for many diseases, such as various ischemic perfusion disorders, inflammatory diseases, diabetes, malignant tumor, arteriosclerosis, neuropathy and the like. Therefore, a substance capable of suppressing generation of active oxygen is considered to be effective for the treatment and prophylaxis of these diseases. Inasmuch as xanthine oxidase has been noted as an enzyme involved in the generation of active oxygen, an inhibitor of xanthine oxidase is expected to suppress generation of active oxygen.
Allopurinol which is a xanthine oxidase inhibitor and known as a therapeutic agent of hyperuricacidemia and gout, as well as a xanthine oxidase inhibitor disclosed in Japanese Patent Unexamined Publication No. 157385/1991 have been studied with regard to the inhibitory effect on organopathy caused by the generation of active oxygen due to ischemic perfusion. The studies are inconclusive since some assert that they are effective for animal models with ischemic perfusion disorder and some assert otherwise. Consequently, a practical use of a substance capable of suppressing generation of active oxygen has not been realized at the present stage.